title: Gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 signaling in pregnant rats.
abstract: Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 (ET-1) signaling. Time-dated pregnant and nonpregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6-21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in nonpregnant rats but significantly increased blood pressure on day 12 (systolic blood pressure, 111.7 ± 6.1 versus 138.5 ± 3.5 mm Hg; P=0.004) and day 20 (systolic blood pressure, 103.4 ± 4.6 versus 125.1 ± 6.1 mm Hg; P=0.02) in pregnant rats and urine protein (μg/μL)/creatinine (nmol/μL) ratio on day 20 (0.10 ± 0.01 versus 0.20 ± 0.04; P=0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma ET-1 levels, as well as the abundance of prepro-ET-1 mRNA, ET-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the ET-1 type A receptor antagonist, BQ123, during the course of hypoxia exposure significantly attenuated the hypoxia-induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened ET-1 and ET-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia.
authors.affiliation: Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhou
authors.forename: Daliao
authors.initials: D
authors.lastname: Xiao
authors.forename: Yali
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Wang
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paradis
authors.forename: Eugenia
authors.initials: E
authors.lastname: Mata-Greenwood
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood*; D005260:Female; D000860:Hypoxia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D011247:Pregnancy; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010456:Peptides, Cyclic; D044140:Receptor, Angiotensin, Type 1; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
keywords: angiotensin II type I receptor; anoxia; endothelin-1; hypertension; preeclampsia; receptor, endothelin A